Clinical and neuropsychological studies of chronically institutionalized elderly patients with schizophrenia indicate a high prevalence of severe cognitive impairment and functional disability. The biological substrates for this dementia are not known. Our preliminary diagnostic neuropathologic investigations have revealed notably few recognized disease states (e.g. Alzheimer's disease) in more than 30 cases to date, although subtle morphometric abnormalities in the hippocampal region and astrocytosis in hippocampal and frontal regions have been observed. The purpose of the proposed research is to investigate the neuronal and molecular substrates of neurodegeneration and dementia in a clinicopathological correlation study of prospectively accrued, well characterized, chronically institutionalized elderly patients with schizophrenia in comparison to Alzheimer disease and non-neuropsychiatric controls. Because of the severity of illness in this population, it may be particularly suitable for this research as neuropathologic abnormalities might be expected to be more evident than in a less afflicted population. Further, if involutional or neurodegenerative processes are an aspect of the pathophysiology of schizophrenia, then these would be most manifest in the elderly. All schizophrenia cases will have been characterized with standardized chart review, clinical diagnostic examinations, and clinical rating scales including the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, Physical Self-Maintenance Scale, Mini-Mental State Examination, and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Battery. Markers of neural injury and degeneration will be identified using histochemical, immunohistochemical and other molecular methods and will be quantified with particle counting and/or optical densitometry using principles of stereology and systematic sampling. Primary regions of interest will be the hippocampus, entorhinal cortex, mid-frontal and orbitofrontal cortices, and primary visual cortex (as an internal control region). Markers will include: a) Alzheimer- related pathology (neurofibrillary tangles and senile plaques identified immunohistochemically); b) astrocytic and microglial proliferation (GFAP immunohistochemistry and RCA-1 lectin histochemistry); c) neuron loss (total Nissl-stained neuron counts in hippocampus, and densities in temporal, frontal and occipital cortices); d) ubiquitination (anti- ubiquitin immunohistochemistry); e) DNA fragmentation (Tdt-mediated dUTP- digoxigenin nick end labeling); and synapse-related protein abnormalities ( synaptophysin, EP-l0, synapsin, chromogranin, GAP-43 immunohistochemistry). Neuropathologic findings will be correlated with antemortem clinical and neuropsychological measures.